Oxetanones

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  and R 2  independently C 1-17  -alkyl which is saturated or optionally interrupted by up to 8 double or triple bonds and/or optionally interrupted by an O or S atom, which is present in other than the α-position to an unsaturated C atom; or phenyl, benzyl or --C 6  H 4  --X--C 6  H 5  ring-substituted by 0 to 3 C 1-6  -alkyl-(O or S) 1  or 0 groups, and X is oxygen, sulfur or (CH 2 ) 0-3 , with the proviso that when R 1  is n-hexyl and R 2  is undecyl or 2Z,5Z-undecadienyl, at least one of the asymmetric C-atoms present in the oxetanone ring and in the β-position to the latter has the R-configuration, an enantiomer or a diastereomer thereof are described. These compounds inhibit pancreas lipase and are useful agents in the treatment of obesity, hyperlipemia, atherosclerosis and arteriosclerosis.

This is a division of application Ser. No. 07/134,322 filed Dec. 17,1987 now U.S. Pat. No. 4,931,463 which is a continuation of Ser. No.06/809,353 filed Dec. 16, 1985 now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to racemic oxetanones of the formula ##STR2##wherein R¹ and R² are independently C₁₋₁₇ -alkyl which is saturated oroptionally interrupted by up to 8 double or triple bonds and/oroptionally interrupted by an O or S atom which is present in a positionother than the α-position to an unsaturated C-atom; or phenyl, benzyl or--C₆ H₄ --X--C₆ H₅ ring-substituted by 0 to 3 C₁₋₆ -alkyl -(O or S)₁ or0 groups, X is oxygen, sulfur or (CH₂)₀₋₃, R³ is hydrogen, C₁₋₃ -alkylor C₁₋₃ -alkanoyl, R⁴ is hydrogen, C₁₋₃ -alkyl, and R⁵ is hydrogen, agroup Ar or Ar--C₁₋₃ -alkyl or C₁₋₇ -alkyl optionally interrupted by Yand optionally substituted by Z, or R⁴ forms with R⁵ a 4- to 6-memberedsaturated ring, Y is oxygen, sulfur or a group N(R⁶), C(O)N(R⁶) orN(R⁶)C(O), Z is a group --(O or S)-- R⁷, --N(R⁷, R⁸), --C(O)N(R⁷,R⁸) or--N(R⁷)C(O)R⁸, n is the number 1 or 0, with the proviso that R⁵ ishydrogen when n is the number 1, Ar is phenyl which is unsubstituted orsubstituted by up to 3 groups R⁹ or OR⁹, and R⁶, R⁷, R⁸ and R⁹individually are hydrogen or C₁₋₃ -alkyl, with the proviso that R⁴ isother than hydrogen when R³ is formyl and R⁵ is isobutyl or R³ is acetyland R⁵ is carbamoylmethyl, and simultaneously R² is undecyl or2,5-undecadienyl and R¹ is n-hexyl, enantiomers or diastereomersthereof, and salts of these oxetanones with weak acids.

The oxetanones of formula I are useful agents for inhibiting pancreaslipase, and accordingly are useful agents in treating obesity,hyperlipaemia, atherosclerosis and arteriosclerosis.

The invention also relates to a process for their preparation,intermediates which are usable in this process as well as medicamentsbased on the said oxetanones or based on precursors thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" denotes a straight or branched chainalkyl containing the number of carbon atoms designated. Examples of C₁-C₁₇ -alkyls are methyl, ethyl, propyl, tertiary butyl, tridecyl and thelike. The term "alkanoyl" denotes a straight or branch chained alkanoylcontaining the number of carbon atoms designated. Examples of C₁ -C₃alkanoyl are formyl, acetyl and the like. The term 4- to 6-membersaturated ring denotes a mono-C₁ -C₃ alkyl substituted or unsubstituted4- to 6-member saturated, nitrogen containing ring, for example,pyrrolidinyl, 4-methylpyrrolidinyl, piperidinyl, and the like. The term"interrupted by an O or S atom or Y" as used in connection with therecitations of R¹, R², R⁴ and R⁵, denotes that the O or S atom or Y is abridging atom or moiety positionly between two carbon atoms within thechain of R¹, R², R⁴ or R⁵ rather than an atom substituted off of thechain of R¹, R², R⁴ or R⁵. Examples of groups interrupted by an O or Satom or Y are methylthioethyl and methyloxyethyl. The term "C₁₋₆-alkyl-(O or S)₁ or O " denotes a C₁₋₆ alkyl optionally having an O orS, such as methyl, ethylthio, and ethyloxy.

The invention relates to racemic oxetanones of the formula ##STR3##where R¹ and R² are independently C₁₋₁₇ -alkyl which is saturated oroptionally interrupted by up to 8 double or triple bonds and/oroptionally interrupted by an O or S atom which is present in a positionother than the α-position to a unsaturated C-atom; or phenyl, benzyl or--C₆ H₄ --X--C₆ H₅ ring-substituted by 0 to 3 C₁₋₆ -alkyl-(O or S)₁ or 3groups, X is oxygen, sulfur or (CH₂)₀₋₃, R is hydrogen, C₁₋₃ -alkyl orC₁₋₃ -alkanoyl. R⁴ is hydrogen or C₁₋₃ -alkyl, and R⁵ is hydrogen, agroup Ar or Ar-C₁₋₃ -alkyl or C₁₋₇ -alkyl optionally interrupted by Yand optionally substituted by Z, or R⁴ forms with R⁵ a 4- to 6-memberedsaturated ring, Y is oxygen, sulfur or a group N(R⁶), C(O)N(R⁶) orN(R⁶)C(O), Z is a group --(O or S)--R⁷, --N(R⁷,R⁸), --C(O) or--N(R⁷)C(O)R⁸, n is the number 1 or 0, with the proviso that R⁵ ishydrogen when n is the number 1, Ar is phenyl which is unsubstituted orsubstituted by up to 3 groups R⁹ or OR⁹, and R⁶, R⁷, R⁸ and R⁹individually are hydrogen or C₁₋₃ -alkyl, with the proviso that R⁴ isother than hydrogen when R³ is formyl and R⁵ is isobutyl or R³ is acetyland R⁵ is carbamoylmethyl, and simultaneously R² is undecyl or2,5-undecadienyl and R¹ is n-hexyl, enantiomers or diastereomersthereof, and salts of these oxetanones with weak acids.

The invention also relates to a process for their preparation,intermediates which are usable in this process as well as medicamentsbased on the said oxetanones or based on precursors thereof.

Preferred oxetanones of the invention are compounds of formula I asdescribed just above wherein R¹ is methyl, propyl, hexyl, decyl,hexadecyl, allyl, benzyl or ethyl; R² is methyl, undecyl, 3-butenyl,3-undecenyl, 8,11-heptadecadienyl, phenoxy or heptadecyl; R³ is acetylor formyl; R⁴ is methyl or hydrogen; and R⁵ is hydrogen, methyl, 2-butylbenzyl, methylthioethyl or i-butyl, or R⁴ and R⁵ together form apyrrolidinyl residue.

Especially preferred oxetanones of the invention are compounds offormula I as described in the paragraph just above wherein R¹ is ethyl.Other especially preferred oxetanones of the invention are compounds offormula I as described in the paragraph just above wherein R² isheptadecyl. Other especially preferred oxetanones of the invention arecompounds of formula I as described in the paragraph just above whereinR³ is formyl. Other especially preferred oxetanones of the invention arecompounds of formula I as described in the paragraph just above whereinR⁴ is hydrogen. Other especially preferred oxetanones of the inventionare compounds of formula I as described in the paragraph just abovewherein R is i-butyl.

Examples of compounds of formula I are:

N-Formyl-L-leucine 1-[(trans-3-ethyl-4-oxo-2-oxetanyl) methyl]dodecylester

N-formyl-L-leucine 1-[(trans-3-allyl-4-oxo-2-oxetanyl) methyl]dodecylester

N-formyl-(S)-leucine(S,9Z,12Z)-1-[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienylester

N-formyl-(S)-leucine(S,Z)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9-octadecenyl esterand

N-formyl-(S)-leucine(R)-α-[[(2S.3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-p-phenoxybenzyl ester.

N-Formyl-(S)-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester is anespecially preferred compound of formula I.

In another aspect the invention relates to racemic oxetanones of theformula ##STR4## wherein R¹ and R² are independently C₁₋₁₇ alkyl whichis saturated or optionally interrupted by up to 8 double or triple bondsand/or optionally interrupted by an O or S atom which is present inother than the α-position to an unsaturated C atom; or phenyl, benzyl or--C₆ H₄ --X--C₆ H₅ ring-substituted by 0 to 3 C₁₋₆ -alkyl-(O or S)₁ or 0groups and X is oxygen, sulfur or (CH₂)₀₋₃, with the proviso that whenR¹ is n-hexyl and R² is undecyl or 2Z-5Z-undecadienyl, at least one ofthe asymmetric C-atoms present in the oxetanone ring and in theβ-position to the latter has the R-configuration, enantiomers ordiastereomers thereof.

Preferred oxetanones of the invention are compounds of formula III asdescribed just above wherein R¹ is methyl, propyl, hexyl, decyl,hexadecyl, allyl, benzyl or ethyl; R² is methyl, undecyl, 3-butenyl,3-undecenyl, 8,11-heptadecadienyl, phenoxy or heptadecyl.

Especially preferred oxetanones of the invention are compounds offormula III as described in the paragraph just above wherein R¹ isethyl. Other especially preferred oxetanones of the invention arecompounds of formula III as described in the paragraph just abovewherein R² is heptadecyl.

Examples of compounds of formula III are:

((3S,4S)-3-Hexyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone;

rac-trans-3-Hexyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]]-2-oxetanone;

cis-3-Hexyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone;

3-Ethyl-4-[(Z)-2-hydroxy-10-nonadecenyl]-2-oxetanone;

rac-trans-3-Allyl-4-[2-hydroxytridecyl]-2-oxetanone; and

trans-3-Hexyl-4-((R)-2-hydroxy-5-tridecenyl)-2-oxetanone.

rac-trans-3-Hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2S,3S, 4S:2R,3R,4R)is an especially preferred compound of formula III.

With weak acids, the oxetanones of formula I form salts which arelikewise an object of the invention. Examples of such acids arep-toluenesulfonic acid, methanesulfonic acid, oxalic acid, ascorbicacid, fumaric acid maleic acid, malic acid, citric acid and phosphoricacid.

The oxetanones of formula I can be prepared by

a) esterifying an acid of the formula ##STR5## which are known compoundsor can be prepared according to known methods, or a functionalderivative thereof with an alcohol of the formula ##STR6## wherein R¹-R⁵ and n are as described above, b) cleaving off the amino protectinggroup W in an oxetanone of the formula ##STR7## wherein R¹, R², R⁴, R⁵and n are as described above, c) if desired, catalytically hydrogenatingunsaturated moieties R¹ and R².

d) if desired, C₁₋₃ -alkanoylating oxetanones of formula I obtained inwhich at least one of R³ and R⁴ is hydrogen and an amino group Y or Zwhich may be present in R⁵ is tertiary, and

e) if desired, isolating oxetanones of formula I obtained in the form oftheir salts with weak acids.

The oxetanones of formula I contain at least 3 asymmetric C atoms andthe oxetanones of formula III can contain one or more asymmetric Catoms. They can accordingly be present as optically active enantiomersas diastereomers or as mixtures, e.g. as racemic mixtures

Unless otherwise indicated, the formulae in the specification are shownas racemates. The compounds of formula I contain at least 3 asymmetric Catoms and the compounds of formula III contain at least 1 assymmetric Catom. The compounds of formulae I and III can accordingly be present asand the invention encompasses optically active enantiomers,diastereomers, as well as racemates.

The esterification a) can be carried out in a solvent, e.g. an ethersuch as tetrahydrofuran (THF), in the presence of triphenylphosphine anddiethyl azodicarboxylate preferably at about room temperature. Thecorresponding anhydride can be used as the functional derivative of anacid of formula II.

Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl can be mentioned asexamples of an amino protecting group W in an oxetanone startingmaterial I'. The cleavage reaction b) can be carried out byhydrogenation in a solvent, e.g. an ether such as THF, in the presenceof a hydrogenation catalyst such as palladium-on-carbon (Pd/C)preferably at room temperature.

The optional hydrogenation (c) can be carried out under analogousconditions to the above-described cleavage reaction b).

The optional C₁₋₃ -alkanoylation d) can be carried out in the presenceof an acid anhydride, e.g a mixed acid anhydride such as formicacid/acetic acid anhydride, in a solvent, e.g. an ether such as THF,preferably at room temperature.

The alcohols III can be prepared by cleaving off the ether protectinggroup L in an ether of the formula ##STR8## wherein R¹ and R² are asdescribed above.

Tetrahydro-2H-pyran-2-yl, 1-ethoxyethyl, benzyl and t-butyldimethylsilylare examples of ether protecting groups L.

The cleavage of the ether protecting group L can be carried out in asolvent e.g. an alcohol such as ethanol, in the presence ofpyridinium-4-toluenesulfonate while heating, e.g. to 50°-65° C.

The ethers IV can be prepared by cyclizing the acids of the formula##STR9## This reaction can be carried out in a solvent such as pyridinewhile cooling, e.g. to 0° C., in the presence of benzenesulfonylchloride.

The acids V can be prepared either

a) by saponifying a corresponding ester of the formula ##STR10## whereinR is C₁₋₄ -alkyl and L, R¹ and R² are as described above, or

b) by condensing an acid of the formula

    R.sup.1 --CH.sub.2 --COOH                                  VII

which are known compounds or can be prepared according to known methods,with an aldehyde of the formula ##STR11##

Methyl, ethyl and t-butyl are examples of alkyl moieties R. Thesaponification a) of an ester VI can be carried out with an alcoholicalkali metal or alkaline earth metal hydroxide solution such as amethanolic potassium hydroxide solution by heating at a temperature upto the reflux temperature of the reaction mixture.

The condensation b) of an acid VII with an aldehyde VIII can be carriedout in a solvent such as THF in the presence of diisopropylamine andbutyl lithium while cooling. e.g. to -50° C.

The acids V, which are present in the (5R)- or (5S)-form, can beconverted in the following manner into 3S,5R)- or(2R,3R.5S)-stereoisomers:

A (5R)- or (5S)-acid of formula V is cyclized, e.g. by means oftoluene-4-sulfonic acid monohydrate while heating 50°-60° C. in ethanol,to the corresponding (6R)- or (6S)-pyranolone of the formula ##STR12##wherein L' is hydrogen and R¹ and R² are as described above.

This (6R)- or (6S)-pyranolone is then oxidized. e.g. in acetone by meansof Jones' reagent at a temperature below 25° C., to the correspondingpyran-2,4-dione and the latter is stereospecifically hydrogenated, e.g.in ethyl acetate in the presence of platinum oxide to the (3S,4S,6R)- or(3R,4R,6S)-pyranolone of formula V-A in which L' is hydrogen. Thispyranolone is converted into a compound of formula V-A in which L'stands for an ether protecting group such as t-butyldimethylsilyl, e.g.by means of t-butyldimethylchlorosilane in dimethylformamide. The cyclic(3S,4S,6R)- or (3R,4R,6S)-ether obtained is cleaved, e.g. by reactionwith an aqueous potassium hydroxide solution in dioxan, and theresulting compound is converted in situ into a (2S 3S.5R)- or(2R.3R.5S)-ether of the formula ##STR13## wherein L" is hydrogen, L' isthe same ether protecting group as in the ether V-A, R¹⁰ is benzyl orp-nitrobenzyl and R¹ and R² are as described above.

The ether V-B obtained is then converted into a diether of the sameformula in which L" stands for an ether protecting group such astetrahydro-2H-pyran-2-yl. After cleaving off firstly the etherprotecting group L', e.g. with tetrabutylammonium fluoride trihydrate inTHF, and then the group R¹⁰, e.g. by hydrogenation in THF in thepresence of Pd/C, there is obtained the desired (2S,3S,5R)- or(2R,3R,5S)-acid of formula V.

The esters VI can be prepared either

a) by alkylating a corresponding ester of the formula ##STR14## or b) byreducing a β-ketoester of the formula ##STR15##

The alkylation a) can be carried out by reacting an ester IX in asolvent such as THF with a solution of n-butyl lithium in a solvent suchas n-hexane in the presence of diisopropylamine at about 50° C. andsubsequently reacting with a solution of an alkyl halide (R¹ -Hal), e.g.a bromide, in hexamethylphosphoric acid triamide at a temperature ofabout 0° to 10° C.

The reduction b) of a 8-ketoester X can be carried out in an inert gassuch as argon in a solvent such as THF with a complex metal hydride suchas sodium borohydride (NaBH₄) at a temperature below 0° C.

The esters IX can be prepared by reductively removing the sulfoxidegroup in a sulfoxide of the formula ##STR16## wherein T is p-tolyl andL, R and R² are as described above.

This reaction can be carried out e.g. by means of aluminum amalgam in asolvent such as THF.

The β-ketoesters X can be prepared by reacting an aldehyde of theformula R² -CHO, which are known compounds or can be prepared accordingto known methods, with a β-ketoester of the formula ##STR17## which areknown compounds or can be prepared according to known methods, andetherifying the resulting alcohol of the formula ##STR18##

The preparation of an alcohol XIII and its etherification can be carriedout as described e.g. in the following Examples H) and J)e),respectively.

Unsaturated moieties R¹ and R² which are present in the intermediates offormula I', III-VI. V-B, X and XIII can be hydrogenated it desired, e.g.under the conditions described above in connection with thehydrogenolytic cleavage of a group W or R¹⁰.

The sulfoxides XI can be prepared by condensing an aldehyde of formulaVIII above with an ester of the formula ##STR19## e.g. as described inExample G). Esters of formula XIV are known compounds or can be preparedin accordance with known methods.

The aldehydes VIII can be prepared by reducing an ester of the formula##STR20## e.g. with a di-(C₁₋₄ -alkyl)-aluminum hydride such asdiisobutylaluminum hydride in a solvent such as toluene at a temperatureof about -60° to -80° C.

The esters of formula XV can be prepared starting from the aldehydes ofthe formula R² -CHO via the sulfoxides of the formula ##STR21## and theesters of the formula ##STR22## e.g. as described in paragraphs F)a), d)and f); G)b), d) and f) and J)b), d) and f) hereinafter.

Further an ester of formula XV in which R² is 3-alkenyl can be preparedby the ozonolysis of an ester of the formula ##STR23## which are knowncompounds or can be prepared according to known methods, and a Wittigreaction with the resulting aldehyde of the formula ##STR24## e.g. asdescribed in Examples K) and L).

(R)-α-(Hydroxydiphenylmethyl)benzyl acetate can be used in place of asulfinyl ester XIV for the conversion of an aldehyde of formula VIII orof an aldehyde of the formula R² -CHO into the corresponding ester offormula IX or XVII. respectively. In this case there is obtained as anintermediate in place of a sulfoxide of formula XI or XVI the(R)-2-hydroxy-1,2,2-triphenylethyl ester corresponding to the alkylesters of formula IX or XVII.

The oxetanones of formula I' can be prepared in the same manner as theoxetanones of formula I, e.g. as described in Example 2.15) hereinafterby esterifying an acid of formula II in which W is present in place ofR³ with an alcohol of formula III. In this esterification there can beused instead of the aforementioned acid the acid anhydride obtained byreaction with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimidehydrochloride or preferably with dicyclohexylcarbodiimide, which can becarried out as described in Example 10 B.1).

The preparation of intermediates of formula IV to XIX is described inmore detail in the following paragraphs A) to M). The compounds reactedas described in paragraphs A) to M), are either known compounds,compounds which can be prepared by known methods, or intermediates ofthe invention such as those of formula IV to XIX.

A) Preparation of the Ethers of Formula IV

A)a) 0.57 g of a diastereomer mixture which consisted, inter alia, of(2S,3S,5R,13Z,16Z)-2-hexyl -3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoic acid was dissolved in 10 ml of pyridine andcooled to 0° C. After the dropwise addition of 0.28 ml ofbenzenesulfonyl chloride the mixture was stirred at 0° C. for a longtime. The reaction mixture was poured into 120 ml of 10 percent aqueoussodium chloride solution and extracted three times with 30 ml of diethylether. The combined extracts were dried, filtered and evaporated. Afterchromatography over silica gel there was obtained a diastereomer mixtureof 3-hexyl-4-[(10Z,13Z)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanones as a colorless oil,IR: 1,815 cm⁻¹.

In an analogous manner,

A)b) 3-Ethyl-4-[(10Z,13Z)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanone, IR: 1,820 cm⁻¹, was obtained

from(13Z,16Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoicacid;

A)c) (3S,4S)-3-ethyl-4-[(R,Z)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-10-nonadecenyl-2-oxetanone was obtained

from (2S,3S,5R,Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoic acid;

A)d) (3-benzyl-4-[(10Z,13Z)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanone, IR: 1,818 cm⁻¹, was obtained

from(13Z,16Z)-2-benzyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoicacid;

A)e)(3S,4S)-3-ethyl-4-[(β)-p-phenoxy-B-((tetrahydro-2H-pyran-2-yl)oxy]phenethyl]-2-oxetanonewas obtained

from(2S,3S,5S)-2-ethyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valericacid;

A)f) (3S,4S)-3-hexyl-4[(S)-p-phenoxy-β-[(tetrahydro-2H-pyran-2-yl)oxy]phenethyl-2-oxetanone, IR: 1,815 cm⁻¹, was obtained

from(2S,3S,5S)-2-hexyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valericacid;

A)g) 3-hexyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanonewas obtained

from 2-hexyl-3-hydroxy-5[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid;

A)h)3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanonewas obtained

from 2-hexyl-3-hydroxy-(R)-5[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid;

A)i) 3-ethyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanonewas obtained

from 2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid;

A)j)3-methyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanonewas obtained

from 2-methyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid;

A)k) 3-allyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanonewas obtained

from 2-allyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid;

A)l) 3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propyl]-2-oxetanonewas obtained

from 2-hexyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexanoicacid;

A)m) 3-hexadecyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]propyl]-2-oxetanonewas obtained

from 2-hexadecyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexanoicacid;

A)n)3-hexyl-4-[(2-[(tetrahydro-2H-pyran-2-yl)oxy]-5-hexenyl]-2-oxetanone wasobtained

from 2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]nonenoic acid;

A)o)3-decyl-4-(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-5-hexenyl]-2-oxetanonewas obtained

from Z-decyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]nonenoicacid;

A)p)3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-5-tridecenyl-2-oxetanonewas obtained

from 2-hexyl-3-hydroxy(R)-5-[tetrahydro-2H-pyran-2-yl)oxy]hexadecenoicacid;

A)q)3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-5-hexenyl]-2-oxetanonewas obtained

from 2-hexyl-3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]nonenoicacid.

(B) Preparation of the Acids of Formula V

B)a) 1.0 g of the diastereomer mixture t-butyl(13Z,16Z)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoatewas heated to reflux in 17 ml of a 2N methanolic potassium hydroxidesolution until the starting material had disappeared. The reactionmixture was cooled and poured on to 60 ml of ice-water. The mixture wasadjusted to pH 1 by the dropwise addition of 1 M aqueous hydrochloricacid and thereupon exhaustively extracted with ether. The combined etherphases were dried, filtered and evaporated. The oil was chromatographedon silica gel, whereby a diastereomer mixture of(13Z,16Z)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran2-yl)oxy]-13,16-docosadienoicacid was obtained an oil, IR: 3,350, 1,709, 1,132, 1,078, 1,023 cm⁻¹.

In an analogous manner,

B)b) (13Z,16Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoic acid was obtained

from t-butyl (13Z,16Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13, 16-docosadienoate;

B)c) (2S,3S,5R,Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoic acid was obtained

from t-butyl (2S,3S,5R,Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-8-yl) oxy]-13-docosenoate:

B)d) (13Z,16Z)-2-benzyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoic acid, MS: 458 (M⁺ -dihydropyran); IR: 3,008,1,709, 1,160, 1,134, 1,115 cm⁻¹, was obtained

from t-butyl (13Z,16Z)-2-benzyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoate;

B)e)(2S,3S,5S)-2-ethyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valeric acid was obtained

from t-butyl(2S,3S,5S)-2-ethyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate;

B)f)(2S,3S,5R)-2-hexyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate was obtained

from t-butyl(2S,3S,5R)-2-hexyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate;

B)g) 2-hexyl-3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid was obtained

from t-butyl2-hexyl-3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate;

B)h) 2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid was obtained

from methyl2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate.

C) Preparation of the Acids V (Variant)

C)a) 2 ml of diisopropylamine in 30 ml of dry THF were cooled to -20° C.and thereupon 9.68 ml of butyl lithium (1.6 M/hexane) were addeddropwise in such a manner that the temperature did not exceed -20° C.The mixture was subsequently stirred for 15 minutes and then cooled to-50° C. Thereafter 0.720 ml of 4-pentenoic acid in 10 ml of THF wasadded dropwise and the mixture was stirred at 50° C. for a further 10minutes. The mixture was stirred at room temperature for 1 hour andsubsequently again cooled to -50° C. 2 g ofrac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal in 10 ml of THF werenow added dropwise and the mixture was stirred at -50° C. for a further30 minutes, then at room temperature for 72 hours. After hydrolysis with2N hydrochloric acid the reaction mixture was evaporated. The residuewas extracted with ether. The organic phase was dried over sodiumsulfate, filtered and evaporated. The material obtained was filteredthrough a column of silica gel. There was obtained2-allyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl) oxy]hexadecanoic acid.

In an analogous manner,

C)b) 2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid was obtained

from rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal and butanoicacid;

C)c) 2-methyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoicacid was obtained

from (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal and propionicacid;

C)d) 2-hexyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexanoic acidwas obtained

from (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]butanal and octanoic acid;

C)e) 2-hexadecyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexanoicacid was obtained

from 3-[tetrahydro-2H-pyran-2-yl)oxy]butanal and octadecanoic acid;

C)f) 2-hexyl-3-hydroxy-(R)-5[(tetrahydro-2H-pyran-2-yl)oxy]-8-nonenoicacid was obtained

from (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-heptenal and octanoic acid;

C)g) 2-decyl-3-hydroxy-(R)-5[(tetrahydro-2H-pyran-2-yl)oxy]-8-nonenoicacid was obtained

from (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-heptenal and dodecanoicacid;

C)h)2-hexyl-3-hydroxy-(R)-5[(tetrahydro-2H-pyran-2-yl)oxy]-8-pentadecenoicacid was obtained

from (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-tetradecenal and octanoicacid;

C)i) 2-hexyl-3-hydroxy-5[(tetrahydro-2H-pyran-2-yl)oxy]-8-nonenoic acidwas obtained

from 3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-heptenal and octanoic acid.

D) Preparation of the Esters of Formula VI

D)a) 3.1 ml of diisopropylamine were cooled to .increment.5° C. underargon and treated dropwise with 14 ml of about 1.6 M n-butyl lithiumsolution in n-hexane. Thereafter the mixture was stirred for 10 minutes.After cooling to -50° C. the cooling bath was removed and a solution of5.08 g of a diastereomer mixture of butyl(13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13.16-docosadienoate in 5 ml of THF was added dropwise. In so doingthe temperature rose to -20° C. The mixture was left to warm to 0° C.and was stirred for 10 minutes. A solution of 2.1 ml of 1-bromohexane in2.5 ml of hexamethylphosphoric acid triamide was then added, whereby thetemperature rose to 9° C. Thereafter, the mixture was left to warm toroom temperature and was stirred for 21/2 hours. The solution was pouredon to 200 ml of ice-water and saturated with sodium chloride. Themixture was extracted with ether. The combined extracts were dried,filtered and evaporated. The residual oil was chromatographed on silicagel. There was obtained a diastereomer mixture of t-butyl(13Z,16Z)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16docosadienoate, MS: 519 (M⁺ -(CH₃)₃ CO.); IR:3,503, 1,728, 1,709, 1,153.

In an analogous manner,

D)b) t-butyl (13Z,16Z)-2-ethyl-3-hydroxy -5-1(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoate. MS: 396 (M⁺ -dihydropyran-isobutylene): IR:3,510, 1,728, 1,153, 1,137 cm⁻¹, was obtained

from t-butyl (13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoate and ethyl iodide;

D)c) t-butyl (13Z,16Z)-2-benzyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoate MS: 525 (M⁺ -(H₃ C)₃ CO.) IR: 3,498, 1,725,1,604, 1,585, 1,496, 1,150 cm⁻¹, was obtained

from t-butyl(13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoateand benzyl bromide;

D)d) t-butyl(2S,3S,5R,Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]docosenoate,MS: 465 (M⁺ -(H₃ C)₃ CO.); IR: 3,499, 1,729, 1,155, 1,137, 1,116, cm⁻¹,was obtained

from t-butyl(3S,5R,Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoate andethyl iodide;

D)e) t-butyl(2S,3S,5R)-2-ethyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2yl)oxy]valerate was obtained

from t-butyl(3S,5R)-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate and ethyl iodide;

D)f) t-butyl(2S,3S,5R)-2-hexyl-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate was obtained

from t-butyl(3S,5R)-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate and 1-bromohexane;

D)g) t-butyl2-hexyl-3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate,D.C. silica gel, hexane-diethyl ether 1:1, Rf=0.65, was obtained

from t-butyl 3-hydroxy(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoateand 1-bromohexane.

E) Preparation of the Esters of Formula VI (Variant)

7.76 g of methyl 2-hexyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate (0.017 mol) weredissolved in 500 ml of THF while gassing with argon, treated with 20 mlof MeOH and cooled to -5° C. 5.3 g of sodium borohydride (0.14 mol) wereadded portionwise while stirring in such a manner that the temperaturedid not exceed 0° C. After stirring for 3 hours the excess sodiumborohydride is filtered off, the reaction mixture was hydrolyzed (to pH6) with 2N hydrochloric acid in the cold and the solvent was evaporatedoff. The residue was extracted with ether and the ethereal phase wasdried and evaporated. There were obtained 7.71 g of methyl2-hexyl-3-hydroxy-5-[(tetrahydro-2 H-pyran-2-yl)oxy]hexadecanoate.

F) Preparation of the Esters of Formula XVII and IX

F)a) 147.6 g of a diastereomer mixture of t-butyl(11Z,14Z)-3-hydroxy-2-[(R)-o-tolylsulfinyl]-11,14-eicosadienoate weredissolved in 5,500 ml of THF and then treated within 6 hours with 190 gof amalgamated aluminum foil. In so doing the temperature was heldbetween 15 and 20° C. After completion of the addition the mixture wasstirred until the reaction had finished. The insoluble material wasfiltered off under suction and washed firstly with 1 l of THF, then with2 l of THF. The filter cake was taken up in 2 l of diethyl ether,stirred and again filtered off under suction. This procedure wasrepeated once. The combined organic phases were evaporated and the oilyresidue Was purified by chromatography on silica gel, whereby there wasobtained an enantiomer mixture which consisted to 80% of

t-butyl (R,11Z,14Z)-3-hydroxy-11,14-eicosadienoate, MS: 324 (M⁺-isobutylene); IR: 3,452, 1,715, 1,154 cm⁻¹.

In an analogous manner,

F)b) t-butyl(13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13,16-docosadienoate,IR: 3,481, 1,730, 1,153, 1,075, 1,014 cm⁻¹, was obtained

from t-butyl (13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-13,14-docosadienoate;

F)c) t-butyl(3S,5R,Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoate,MS: 437 (M⁺ -(H₃ C)₃ CO); IR: 3,484, 1,730, 1,655, 1,153, 1,075, 1,024cm⁻¹, was obtained

from t-butyl (3S,5R,Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-13-docosenoate;

F)d) t-butyl (R,Z)-3-hydroxy-11-eicosenoate, IR: 3,445, 1,716, 1,154cm⁻¹, was obtained

from t-butyl (R,Z)-3-hydroxy-2-[(R)-p-tolylsulfinyl]-11-eicosenoate;

F)e) t-butyl (3S5S)-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]valerate, MS: 357 (M⁺ -tetrahydropyranyl); IR: 3,446, 1,727, 1,590,1,505, 1,489, 1,152, 1,133, 1,118, 1,074, 1,022, cm⁻¹, was obtained

from t-butyl(3S,5S)-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-o-tolylsulfinyl]valerate;

F)f) t-butyl [(S)-α-hydroxy-p-phenoxybenzyl]acetate, m.p. 64°-65° C.(from n-hexane), MS: 314 (M⁺); IR: 3,440, 1,713, 1,590, 1,506, 1,491,1,158, was obtained

from t-butyl (βS)-S-hydroxy-p-phenoxy-α-[(R)-p-tolylsulfinyl-hydrocinnamate;

F)g) t-butyl3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate wasobtained

from t-butyl3-hydroxy-(R)-5-tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]hexadecanoate.

G) Preparation of the Sulfoxides of Formula XI and XVI

G)a) 16.5 g of t-butyl [(S)-p-tolylsulfinyl]acetate were dissolved in amixture of 600 ml of ether and 60 ml of THF and cooled to -78° C. 43 mlof t-butylmagnesium bromide were then added dropwise in such a mannerthat the temperature remained below -70° C. After stirring at -78° C.for 1 hour 13.4 g of (R)-3-[(tetrahydro-2H-pyran-2yl)oxy]-tetradecanalin 100 ml of THF were added dropwise. After 2 hours at -78° C. thereaction mixture was hydrolyzed with 2N hydrochloric acid and thesolvent was evaporated off. The reaction mixture remaining behind wasextracted with ether and the ethereal phase was dried and evaporated.After chromatography on silica gel there were obtained 14.9 g of t-butyl3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-hexadecanoate (67% yield). m.p. 97°-98° C.

In an analogous manner,

G)b) t-butyl(3R,11Z,11Z)-3-hydroxy-2-[(R)-p-tolylsulfinyl]-11,14-eicosadienoate, IR:3,400, 1,727, 1,653, 1,596, 1,494, 1,279, 1,258, 1,115, 1,085, 1,045cm⁻¹, was obtained

from 9,12-octadienal and t-butyl (R)-p-tolylsulfinyl-acetate;

G)c) t-butyl (13Z,16Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-13,16-docosadienoate was obtained

from t-butyl(11Z,14Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11,14-eicosadienal andt-butyl (S;-p-tolylsulfinyl-acetate;

G)d) t-butyl (R,Z)-3-hydroxy-2-[(R)-p-tolylsulfinyl]-11-eicosenoate, MS:464 (M⁺ isobutylene), IR: 3,403, 1,727, 1,596, 1,494, 1,145, 1,043 cm⁻¹,was obtained

from 9-octenal and t-butyl (R)-p-tolylsulfinyl-acetate;

G)e) t-butyl(3S,5R,Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)-oxy]-2-[(S)-p-tolylsulfinyl-13-docosenoatewas obtained

from t-butyl (R,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenal and(S)-p-tolylsulfinyl-acetate;

G)f) t-butyl(βS)-β-hydroxy-p-phenoxy-α-[(R)-p-tolylsulfinyl]-hydrocinnamate, m.p.126°-128° C. (from n-hexane). was obtained

from t-butyl p-phenoxy-benzaldehyde and (R)-p-tolylsulfinyl-acetate;

G)g) t-butyl(3S,5S)-3-hydroxy-5-(p-phenoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]valerate, m.p. 140°-145° C., was obtained

from t-butyl(BS)-p-phenoxy-8-[(tetrahydro-2H-pyranyl)oxy]-hydrocinnamaldehyde andt-butyl (S)-p-tolylsulfinyl-acetate.

H) Preparation of the Alcohols of Formula XIII

5 g of a 55% sodium hydride dispersion were washed with hexane andtreated with 600 ml of THF. 18.9 g of methyl 2-acetyloctanoate dissolvedin 80 ml of THF were added dropwise while cooling. After stirring for 2hours the mixture was cooled to -10° C. and treated while cooling with65 ml of butyl lithium (1.6M hexane). After 1 hour at -10° C. a solutionof 19.7 q of dodecanal in 80 ml of THF was added dropwise. The mixturewas left to warm to room temperature and stirred for a further 2 hours.The reaction mixture was hydrolyzed with 100 ml of 2N hydrochloric acidand evaporated. The residue was extracted with ether and the etherealphase was dried and evaporated. After chromatography on silica gel therewas obtained methyl 2-hexyl-5-hydroxy-3-oxohexadecanoate, m.p. 38°-39°C.

I) Preparation of the Aldehydes of Formula VIII

I)a) 9.2 g of t-butyl(R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate were dissolved in115 ml of toluene while gassing with argon and with the exclusion ofmoisture and cooled to -75° C. 26.5 ml of a 1.2 M solution ofdiisobutylaluminum hydride in toluene were then added dropwise in such amanner that the temperature did not exceed -70° C. After stirring at-75° C. for 1 hour there were added dropwise 7.4 ml of saturated aqueousammonium chloride solution and subsequently 15.5 ml of 1N hydrochloricacid at -70° C. The mixture was then left to warm to room temperature.After stirring for 1 hour the organic phase was dried, filtered andevaporated. The material obtained was chromatographed on silica gel.There was obtained (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal asa colorless oil.

In an analogous manner,

I)b) rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal was obtained

from methyl rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate;

I)c) (11Z,14Z)-3-[(tetrahydro -2H-pyran-2-yl)oxy]-11,14-eicosadienal MS:291 (M⁺ -2-tetrahydropyranyloxy), 290 (M⁺ -tetrahydro-2-pyranol), IR:2,729, 1,726, 1,132, 1,118, 1,077 cm⁻¹, was obtained

from t-butyl(11Z,14Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11,14-eicosadienoate;

I)d) (R,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosanal, MS: 292 (M⁺-tetrahydro-2-pyranol); IR: 2,722, 1,726, 1,132, 1,118, 1,077 cm⁻¹, wasobtained

from t-butyl (R,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosanoate;

I)e) (βS)-p-phenoxy-β-[(tetrahydro-2H-pyran-2-yl)oxy]hydrocinnamaldehydewas obtained

from t-butyl[(S)-p-phenoxy-α-[(tetrahydro-2H-pyran-2-yl)oxy]benzyl]acetate;

I)f) (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6Z-tetradecenal was obtained

from ethyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6H-tetradecenoate.

J) Preparation of the Esters of Formula XV

J)a) 66.5 g of t-butyl (R,11Z,14Z)-3-hydroxy-11,14-eicosadienoate, whichcontained about 20% of the (S)-isomer, and 32 ml of freshly distilled3,4-dihydro-2H-pyran were dissolved in 650 ml of methylene chloride andcooled to 3° C. Thereafter, 640 mg of p-toluenesulfonic acid monohydratewere added, whereby the temperature rose to 8° C. The mixture wasstirred until the reaction was finished. Thereupon, the solution waswashed with a mixture of 250 ml of saturated aqueous sodium chloridesolution, 250 ml of saturated aqueous sodium hydrogen carbonate solutionand 500 ml of water. After drying the mixture was filtered and thesolvent was removed. The oily residue was purified by chromatography onsilica gel. There was obtained a diastereomer mixture of t-butyl(11Z,14Z)-3-[(tetrahydro -2H-pyran-2-yl)oxy]-11,14-eicosadienoate. MS:324 (M⁺ -dihydropyran-isobutylene); IR: 1,731, 1,158, 1,024 cm⁻¹.

In an analogous manner,

J)b) t-butyl (R,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenoate, MS:326 (M⁺ -dihydropyran-isobutylene), IR: 1,731, 1,158, 1,134, 1,118 cm⁻¹,was obtained

from t-butyl (R,Z)-3-hydroxy-11-eicosenoate and dihydropyran;

J)c) t-butyl[(S)-p-phenoxy-α-[(tetrahydro-2H-pyran-2-yl)oxy]benzyl]acetate, MS: 313(M⁺ -tetrahydropyranyl); IR: 1,730, 1,590, 1,506, 1,489, 1,391, 1,367,1,201, 1,149, 1,118 cm⁻¹, was obtained

from t-butyl [(S)-α-hydroxy-p-phenoxybenzyl]acetate and dihydropyran;

J)d) methyl rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate. D.C.silica gel, hexane ether 3:1, Rf=0.67, was obtained

from methyl rac-3-hydroxytetradecanoate and dihydropyran;

J)e) methyl2-hexyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate, m.p.37°-38° C., was obtained

from methyl 2-hexyl-5-hydroxy-3-oxo-hexadecanoate and dihydropyran.

K) Preparation of an Ester of Formula XV (Variant)

K)a) A solution of 0.51 g of diisopropylamine in 20 ml of THF wastreated at 0° C. with 3.13 ml of a 1.6 molar solution of butyl lithiumin hexane. The mixture was then cooled to -78° C. and 2.3 g ofheptyltriphenylphosphonium bromide were added thereto and the mixturewas left at this temperature for 5 minutes. A solution of ethyl5-formyl-(R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentanecarboxylate in 10ml of THF was subsequently added dropwise. The mixture was left to stirat room temperature overnight. The reaction mixture was treated withwater, extracted with ether, dried and evaporated in vacuo. The residuewas chromatographed over silica gel with toluene-ethyl acetate (9:1) andthere was obtained 0.5 g of ethyl(R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6Z-tetradecenecarboxylate.

K)b) In an analogous manner there was obtained:

Ethyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6Z-eicosenecarboxylate.

L) Preparation of an Aldehyde of Formula XIX

A solution of 2.56 g of methyl(R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-6-heptenoate in 40 ml of ethylacetate was treated with ozone at -75° C. After completion of thereaction 0.1 g of Pd-on-carbon was added thereto and the mixture washydrogenated at room temperature. After the hydrogen uptake was finishedthe catalyst was filtered off and washed with ethyl acetate and thefiltrate and washings were evaporated in vacuo There was obtained methyl5-formyl-(R)-3-[(tetrahydro-2H-pyran-2- yl)oxy]-pentanecarboxylate.

Separation of the Acids of Formula V Into Their Stereoisomers

M)a) 15.4 g of a diastereomer mixture of2-hexyl-3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-b 2-yl) oxy]hexadecanoicacid were dissolved in 160 ml of ethanol and 800 mg oftoluene-4-sulfonic acid monohydrate were added. The reaction mixture washeated to 55°-60° C. until the reaction was finished. The solvent wasremoved in vacuo and the residue was dissolved in 160 ml ofdichloromethane. The solution was stirred at room temperature for 1hour. The reaction mixture was evaporated. The material obtained waschromatographed on silica gel. There was obtainedtetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2 H-pyran-2-one. m.p. 95°-96°C.

M)b) 3 g of a diastereomer mixture oftetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-2-one were dissolvedin 300 ml of acetone. 3 ml of Jones' reagent were added dropwise whilestirring in such a manner that the temperature did not exceed 25° C.After 3 hours the reaction mixture was poured into 700 ml of H₂ O. Thelactone precipitated out and was filtered off. After recrystallizationin ether/n-hexane there were obtained 1.7 g oftetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one, m.p.112.5°-113.5° C.

M)c) 8 g of an isomer mixture oftetrahydro-3-hexyl-4-oxo-(R)-6-undecyl-2H-pyran-2-one were dissolved in2 l of ethyl acetate and 3 g of PtO₂ were added. The mixture was thenhydrogenated (50 bar) for 12 hours. The catalyst was filtered off andthe solution was evaporated. After recrystallization there were obtained7 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2 H-pyran2-one. m.p. 108°-109° C.

M)d) 1.5 g of(3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one weredissolved in 8 ml of DMF. 0.85 g of t-butyldimethylchlorosilane in 4 mlof DMF were then added dropwise. The mixture was stirred for 48 hours.The reaction mixture was poured in to 100 ml of ether and washed with 1Nhydrochloric acid. The organic phase was dried, filtered and evaporated.The material obtained was chromatographed on silica gel. There wereobtained 1.26 g of(3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one,MS: 411 (M⁺ -t-butyl).

M)e) 0.3 g of(3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one was dissolved in mixture of 12 ml of dioxan and 0.64 ml of1N aqueous potassium hydroxide. The mixture was stirred overnight. Thereaction mixture was then evaporated and the residue was dissolved in 10ml of hexamethylphosphortriamide. 0.35 ml of benzyl bromide was added.The mixture was stirred for 2 days. The reaction mixture was poured intowater and extracted with ether. The ether phase was dried, filtered andevaporated. The oil was chromatographed on silica gel. There wereobtained 330 mg of benzyl(2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-hydroxyhexadecanoate,MS: 519 (M⁺ -t-butyl).

M)f) 350 mg of benzyl(2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-hydroxyhexadecanoateand 0.5 ml of freshly distilled 3,4-dihydro-2H-pyran were dissolved in10 ml of methylene chloride and cooled to -15° C. A crystal ofp-toluenesulfonic acid monohydrate was added thereto. The mixture wasstirred until the reaction has finished. Thereupon, the solution wasevaporated and the residue was chromatographed on silica gel. There wereobtained 330 mg of benzyl(2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate, MS: 603 (M⁺ -t-butyl).

M)g) 480 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate and 350 mg oftetrabutylammonium fluoride trihydrate were dissolved in 8 ml of THF andstirred for 12 hours. After evaporation the residue was dissolved in 50ml of ether and washed with water. The ethereal phase was dried andevaporated. The product was chromatographed on silica gel. There wereobtained 240 mg of benzyl(2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro2H-pyran-2-yl) oxy]hexadecanoate, MS: 463 [(M+H)⁺ -dihydro-2H-pyran-2-yl].

M)h) 430 mg of benzyl (2S,3S,5R)-2-hexyl-3-hydroxy 5-[(tetrahydro-2H-pyran-2-yl) oxy]hexadecanoate in 10 ml of THF were treated with Pd/C10% and hydrogenated for 3 hours. The catalyst was filtered off and,after evaporation of the filtrate, the product was chromatographed onsilica gel. There was obtained(2S,3S,5R)-2-hexyl-3hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid.

The alcohols of formula III in which R¹ and R² are as described above,with the proviso that when R¹ is n-hexyl and R² is undecyl or2Z,5Z-undecadienyl, at least one of the asymmetric C-atoms present inthe oxetanone ring and in the β-position to the latter has theR-configuration, are within the scope of the invention.

Preferred oxetanones of formula I and III are those in which R¹ ismethyl propyl, hexyl, decyl, hexadecyl, allyl, benzyl or especiallyethyl; R² is methyl, undecyl, 3-butenyl, 3 undecenyl,8,11-heptadecadienyl, phenoxyphenyl or especially heptadecyl; R³ isacetyl or especially formyl: R⁴ is methyl or especially hydrogen and R⁵is hydrogen, methyl 2-butyl, benzyl methylthioethyl or especiallyi-butyl, or R⁴ and R⁵ together form a pyrrolidinyl residue.

The oxetanones of formula I and III have valuable pharmacologicalproperties. In particular, they inhibit pancreas lipase and canaccordingly be used in the control or prevention of obesity,hyperlipaemia, atherosclerosis or arteriosclerosis.

The inhibition of pancreas lipase by the oxetanones of formula I and IIIcan be demonstrated experimentally by registering titrimetrically theoleic acid liberated in the cleavage of triolein by pig pancreas lipase.To an emulsion which contains 1 mM of taurodeoxycholate 9 mM oftaurocholeate 0.1 mM of cholesterol 1 mM of egg lecithin, 15 mg/ml ofBSA, 2 mM of Tris HCl, 100 mM of sodium chloride, 1 mM of calciumchloride and triolein as the substrate was added the compound of formulaI dissolved in ethanol or dimethyl sulfoxide (10% of the emulsionvolume) and the reaction was started by the addition of 100 μg (175 U)of pig pancreas lipase. The pH was held at 8 during the reaction by theaddition of sodium hydroxide solution. The IC₅₀ was calculated from theconsumption of sodium hydroxide solution determined during 10 minutes.The IC₅₀ was that concentration at which the lipase activity wasinhibited to half of the maximum. The following Table contains theIC.sub. 50 values determined for the compounds of formula I and III anddata concerning the acute toxicity (toxicity after single oraladministration to mice, expressed in dose of the compound at which theanimal survives).

                  TABLE                                                           ______________________________________                                        Test compound    IC.sub.50 in                                                                          Toxicity in                                          in:              μg/ml                                                                              mg/kg p.o.                                           ______________________________________                                        Example 1b)      19                                                           Example 2, 13)a) 0.007                                                        Example 2, 14)   0.015   5000                                                 Example 2, 21)   0.02                                                         Example 2, 23)a) 0.035   2000                                                 Example 2, 25)a) 0.01                                                         Example 2, 34)   0.13    4000                                                 Example 4, 1)    0.011                                                        Example 5        0.20                                                         Example 6, 2)    1.0                                                          Example 7        15                                                           Example 9 F.2.   85                                                           ______________________________________                                    

The oxetanones of formula I and III can be used as medicaments, e.g. inthe form of pharmaceutical preparations. The pharmaceutical preparationscan be administered orally, e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatine capsules, solutions, emulsions orsuspensions.

For the preparation of pharmaceutical preparations the products inaccordance with the invention can be processed with pharmaceuticallyinert inorganic or organic carrier materials. As such carrier materialsthere can be used for tablets, coated tablets dragees and hard gelatinecapsules for example lactose maize starch or derivatives thereof talcstearic acid or its salts and the like. Suitable carrier materials forsoft gelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like, depending on the nature ofthe active substance no carrier materials are, however, generallyrequired in the case of soft gelatine capsules. Suitable carriermaterials for the manufacture of solutions and syrups are, for example,water, polyols, saccharose, invert sugar, glucose and the like.

Moreover, the pharmaceutical preparations can contain preserving agents,solubilizers, stabilizing agents, wetting agents, emulsifying agents,sweetening agents, coloring agents, flavoring agents, salts for varyingthe osmotic pressure, buffers, coating agents or antioxidants. They canalso contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing an oxetanone of formula Ior III were likewise an object of the present invention as is a processfor the manufacture of such medicaments, which process comprisesbringing an oxetanone of formula I or III and if desired, one or moreother therapeutically valuble substances into a galenical administrationform. As mentioned, the compounds of formula I and III can be used toinhibit pancreas lipase by administration of an effective amount to ahost requiring such treatment. Accordingly, the compounds of formula Iand III can be used in the treatment, that is, in the control orprevention of illnesses, especially in the control or prevention ofobesity, hyperlipaemia, atherosclerosis and arteriosclerosis, byadministration of an effective amount to a host requiring suchtreatment. The dosage can vary within wide limits and is, of course,fitted to the individual requirements in each particular case. Ingeneral, in the case of oral administration a daily dosage of about 0.1mg to 100 mg/kg body weight should be appropriate

The oxetanones of formula I or III can also be added toindustrially-produced foodstuffs, whereby fats, oils, butter, margarine,chocolate and other confectionery goods especially come intoconsideration. Such industrially-produced foodstuffs which can containabout 0.1 to 5 wt % of an oxetanone of formula I or III, and theirmanufacture are likewise objects of the present invention.

The following Examples were intended to illustrate the present inventionin more detail but they are not intended to limit its extent in anymanner. All temperatures are given in degrees Celsius.

EXAMPLE 1

44.3 ml of diethyl azodicarboxylate were added dropwise while stirringto a solution of 100 mg ofrac-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2R,3S,4S: 2S,3R,4R), 74 mgof triphenylphosphine and 45 mg of N-formyl-D-leucine in 2 ml of THF.After stirring overnight the organic phase was evaporated in vacuo andthe residue was purified by chromatography on silica gel withtoluene-ethyl acetate (9:1). There were obtained

1.a) N-formyl-D-leucine(R)-1-[[(2R.3R)-3-hexyl-4-oxo-2-oxetanyl]methyl]dedecyl ester and

1.b) N-formyl-D-leucine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester.

EXAMPLE 2

Analogously to Example 1,

2.1) by esterifying rac-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2R,3R,4R;2S,3S,4S) with N formyl-D-leucine there were obtained

2.1)a) N-formyl-D-leucine(S)-1-[[(2R,3R)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester and

2.1)b) N-formyl-D-leucine(R)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester;

2.2) by esterifying rac-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2S,3R,4R:2R,3S,4S) with N-formyl-L-leucine there was obtained

N-formyl-L-leucine(R)-1-[[(2R,3R)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]_(D)²⁵ =-2.2° (methanol, c=0.9%);

2.3) by esterifying rac-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2S,3S,4S:2R 3R,4R) or(3R,4R)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone withN-formyl-L-leucine there were obtained

2.3)a) N-formyl-L-leucine(R)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]_(D)²⁵ =-19.4° (methanol, c=0.35%), and

2.3)b) N-formyl-L-leucine(S)-1-[[(2R,3R)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]_(D)²⁵ =-2.87° (methanol, c=0.8%);

2.4) by esterifying rac-cis-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(enantiomer pair A) with N-formyl-L-leucine there were obtained

2.4)a) N-formyl-L-leucine1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester D.C. silica gel;toluene-ethyl acetate 2:1, RF=0.55, and

2 4)b) N-formyl-L-leucine1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester. D.C. silica gel;toluene-ethyl acetate 2:1, RF=0.47;

2.5) by esterifying rac-cis-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(enantiomer pair B) with N-formyl-L-leucine there were obtained

2.5)a) N-formyl-L-leucine1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester, D.C. silica gel;toluene-ethyl acetate 2:1 RF=0.53, and

2.5)b) N-formyl-L-leucine1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester, D.C. silica gel:toluene-ethyl acetate 2:1, RF=0.50;

2.6) by esterifying(3S,4S)-3-hexyl-4,-[(R)-2-hydroxytridecyl]-2-oxetanone withN-formylglycine there was obtained

N-formylglycine (S)-1-(2S,3S)-[(3-hexyl-4-oxo-2-oxetanyl)methyl]dodecylester, [α]_(D) ²⁵ =-22° (CHCl₃, c=0.88);

2.7) by esterifying trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone withN-formylglycine there was obtained

N-formylglycine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester,D.C. silica gel, diethyl ether-hexane 9:1, RF=0.34;

2.8) by esterifying rac-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2R,3S,4S:2S,3R,4R) with N-acetyl-L-leucine there was obtained

N-acetyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecylester, D.C. silica gel; CHCl₃ : hexane:dioxan 1:3:0.25, RF=0.36;

2.9) by esterifying(3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone withN-formyl-β-alanine there was obtained

N-formyl-β-alanine (S)-1-(2S,3S)[(3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester, D.C. silica gel;toluene-ethyl acetate 2:1, RF=0.39;

2.10) by esterifying trans-3-hexyl-[(S)-2-hydroxypropyl]-2-oxetanone(3S,4S:3R,4R) with N-formyl-L-leucine there was obtained

N-formyl-L-leucine (S)-1-[(3-hexyl-4-oxo-2-oxetanyl)methyl]ester, D.C.silica gel, toluene-ethyl acetate 2:1, RF=0.27;

2.11) by esterifying 3-methyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone(3R,4R:3S,4S) with N-formyl-L-leucine there was obtained

N-formyl-L-leucine (S)-1-[(3-methyl-4-oxo-2-oxetanyl)methyl]dodecylester, D.C. silica gel, toluene-ethyl acetate 2:1, RF=0.34;

2.12) by esterifyingrac-trans-3-hexadecyl-4-(2-hydroxypropyl)-2-oxetanone withN-formyl-L-leucine there was obtained

N-formyl-L-leucine 1-[(trans-3-hexadecyl-4-oxo-2 oxetanyl)methyl]ethylester, M.S.: 496 (M⁺ ; D.C. silica gel, toluene-ethyl acetate 2:1,RF=0.44;

2.13) by esterifying rac-trans-3 ethyl-4-(2-hydroxytridecyl)-2-oxetanonewith N-formyl-L-leucine there were obtained

2 13)a) N-formyl-L-leucine1-[(trans-3-ethyl-4-oxo-2-oxetanyl)methyl]dodecyl ester. D.C. silicagel, toluene-ethyl acetate 2:1, RF=0.62, and

2.13)b) N-formyl-L-leucine1-[(trans-3-ethyl-4-oxo-2-oxetanyl)methyl]dodecyl ester, D.C. silicagel, toluene-ethyl acetate 2:1, RF=0.55;

2.14) by esterifying rac-trans-3-allyl-4-(2-hydroxytridecyl)-2-oxetanonewith N-formyl-leucine there was obtained

N-formyl-L-leucine 1-[(trans-3-allyl-4-oxo-2-oxetanyl)methyl]dodecylester, I.R.: 1,825, 1,739, 1,688; D.C. silica gel, toluene-ethyl acetate2:1. RF=0.58;

2.15) by esterifying rac-trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanonewith N-benzylcarbamoyl-leucine there was obtained

N-benzylcarbamoyl-leucine1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester, D.C. silicagel, hexane-diethyl ether 1:1. RF=0.64;

2.16) by esterifying (3S,4S)-3-hexyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl)-2-oxetanone with formyl-(S)-leucine there wasobtained

N-formyl-(S)-leucine(S,9Z,12Z)-1-[[(2S,3S)-3-hexyl-1-oxo-2-oxetanyl]methyl]-9,12-octadienyl ester. M.S.: 575 (M⁺); I.R.: 1,824, 1,739, 1,675 cm⁻¹ ;

2.17) by esterifying rac-trans-3-hexyl-4-[(10Z,13Z)-2 hydroxy-10,13-nonadecadienyl]-2-oxetanone(2R,3R,4R:2S,3S,4S) withN-formyl-(S)-leucine there was obtained

N-formyl-(S)-leucine(9Z,12Z)-1-(trans-3-hexyl)-4-oxo-2-oxetanyl)methyl]octadecadienyl ester(2 diastereomers),

M.S.: 575 (M⁺): I.R.: 1,824, 1,740, 1,687 cm⁻¹ ;

2.18) by esterifyingcis-3-hexyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone(diastereomer mixture) with N-formyl-(S)-leucine there were obtained

2.18)a) N-formyl-(S)-leucine (9Z,12Z)-1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]-9,12-octadienyl ester (diastereomer mixture I), M.S.: 575 M⁺);I.R.: 1,823, 1,739, 1,674 cm⁻¹, and

2.18)b) N-formyl-(S)-leucine (9Z,12Z)-1-[(cis-3-hexyl-4-oxo-2-oxetanyl)methyl]-9,12-octadienyl ester (diastereomer mixture II), M.S.: 372 (M⁺-N-formyl-leucine-CO₂); I.R.: 1,822, 1,739, 1,684, cm⁻¹ ;

2.19) by esterifying (3S,4S)-3-benzyl-4-[(R,10Z,13Z)-2-hydroxy-10,13-nonadecadienyl)]-2-oxetanone with N-formyl-(S)-leucine there wasobtained

N-formyl-(S)-leucine(S,9Z,12Z)-1-[[(2S,3S)-3-benzyl-4-oxo-2-oxetanyl]methyl]-9,12-octadienyl ester, M.S.: 581 (M⁺); I.R.: 1,825, 1,739, 1,683 cm⁻¹ ;

2.20) by esterifyingrac-trans-3-benzyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone(2R,3R,4S;2S,3S,4S)with N-formyl-(S)-leucine there were obtained

2.20)a) N-formyl-(S)-leucine(9Z,12Z)-1-((trans-3-benzyl-4-oxo-2-oxetanyl)methyl]-9,12-octadecadienyl ester (diastereomer I). M.S.: 581 M⁺); I.R.: 1,825,1,739, 1,676 cm⁻¹, and

2.20)b) N-formyl-(S)-leucine(9Z,12Z)-1-[(trans-3-benzyl-4-oxo-2-oxetanyl)methyl]-9,12-octadeoadienyl ester (diastereomer II), M.S.: 581 M⁺); I.R.: 1,824,1,740, 1,687 cm⁻¹ ;

2.21) by esterifying trans-3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (diastereomer mixture) withN-formyl-(S)-leucine there was obtained

N-formyl-(S)-leucine(S,9Z,12Z)-1-[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienyl ester. M.S.: 519 (M⁺); I.R.: 1,825, 1,739, 1,684 cm⁻¹;

2.22) by esterifying cis-3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone with N-formyl-(S)-leucine (enantiomermixture B) there was obtained

N-formyl-(S)-leucine(9Z,12Z)-1-[[cis-3-ethyl-4-oxo-2-oxetanyl]methyl]-9, 12-octadecadienylester (diastereomer mixture), M.S.: 316 (M⁺ -N-formyl-leucine-CO₂);I.R.: 1,825, 1,739, 1,677 cm⁻¹ ;

2.23) by esterifying(3S,4S)-3-ethyl-4-[(R,Z)-2-hydroxy-10-nonadecenyl]-2-oxetanone withN-formyl-S-leucine there were obtained

2.23)a) N-formyl-(S)-leucine(S,Z)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9-octadecenyl ester(diastereomer I), M.S.: 521 (M⁺); I.R.: 1,825, 1,739, 1,673 cm⁻¹, and

0 2.23)b) N-formyl-(S)-leucine(Z)-1-[(trans-3-ethyl-4-oxo-2-oxetanyl)methyl]-9-octadecenyl ester

2.24) by esterifying(3S,4S)-3-hexyl-4-[(S)-β-hydroxy-p-phenoxyphenethyl]-2-oxetanone withN-formyl-(S)-leucine there was obtained

N-formyl-(S)-leucine α-[[(2S,3S)-3hexyl-4-oxo-2-oxetanyl]methyl]-p-phenoxybenzyl ester (diastereomermixture), M.S.: 509 (M⁺); I.R.: 1,821, 1,742, 1,686 cm⁻¹ ;

2.25) by esterifying(3S,4S)-3-ethyl-4-[(S)-β-hydroxy-p-phenoxyphenethyl]-2-oxetanone withN-formyl-(S)-leucine there were obtained

2.25)a) N-formyl-(S)-leucine(R)-α-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-p-phenoxybenzyl ester,M.S.: 453 (M⁺); I.R.: 1,824, 1,742, 1,686 cm⁻¹, and

2.25)b) N-formyl-(S)-leucine(S)-α-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-p-phenoxybenzyl esterM.S.: 453 (M⁺); I.R.: 1,823, 1,743, 1,686 cm⁻¹ ;

2.26) by esterifyingrac-trans-3-hexyl-4-(2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-leucine there was obtained

N-formyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenylester (mixture of 2 diastereomers);

2.27) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-leucine there was obtained

N-formyl-L-leucine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester:

2.28) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl(S)-valine there was obtained

N-formyl-(S)-valine1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester;

2.29) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-isoleucine there was obtained

N-formyl-L-isoleucine(S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester;

2.30) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-phenylalanine there was obtained

N-formyl-phenylalanine(S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester;

2.31) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-alanine there was obtained

N-formyl-L-alanine (S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl)-4-pentenylester;

2.32) by etherifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone withN-formyl-L-proline there was obtained

N-formyl-L-proline(S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester;

2.33) by esterifying(S)-3-hexyl-(S)-4-[(R,Z)-2-hydroxy-5-tridecenyl)-2-oxetanone withN-formyl-L-leucine there was obtained

N-formyl-L-leucine(S,Z)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-dodecenyl ester;

2.34) by esterifying(S)-3-decyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl Lleucine there was obtained

N-formyl-L-leucine(S)-1-[[(2S,3S)-3-decyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester;

2.35) by esterifying(S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl]-2-oxetanone withN-formyl-L-methionine there was obtained

N-formyl-L-methionine(S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester;

2.36) by esterifying3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl)-2-oxetanone withN-formyl-N-methyl-L-leucine there was obtained

N-formyl-N-methyl-L-leucine(9Z,12Z)-1-[(3-ethyl-4-oxo-2-oxetanyl)methyl]-9,12-octadienyl ester.

EXAMPLE 3

A solution of 27 mg of N-formyl-(S)-leucine(S,9Z,12Z)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-9,12-octadienylester in 1 ml of THF was added to 4.4 mg of 10% Pd/C. The mixture washydrogenated at room temperature until the reaction was finished. Thecatalyst was filtered off and the solvent was removed in vacuo. Afterdrying in vacuo there was obtained N-formyl-(S)-leucine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyloctadecyl ester as whitecrystals, m.p. 64°-65° C.

EXAMPLE 4

Analogously to Example 3,

4.1) from N-formyl-(S)-leucine(S,9Z,12Z)-1-[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]-9,12-octadecadienylester there was obtained

N-formyl-(S)-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester as whitecrystals. m.p. 48°-53° C.;

4.2) from N-formyl-L-leucine1-[(trans-3-allyl-4-oxo-2-oxetanyl]methyl]dodecyl ester there wasobtained

N-formyl-L-leucine 1-[(trans-3-propyl-4-oxo-2-oxetanyl]methyl]dodecylester.

EXAMPLE 5

A solution of 10 mg of N-formyl-L-leucine1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester in 0.5 ml ofTHF was treated with 2.5 mg of 5% Pd/C and hydrogenated. After thehydrogen uptake was finished the catalyst was filtered off and thefiltrate was evaporated in vacuo. The residue was chromatographed oversilica gel with toluene/ethyl acetate (8:2) and there was obtainedamorphous N-formyl-L-leucine1-[(trans-3-hexyl-4-oxo2-oxetanyl]-methyl]pentyl ester as a mixture of 2diastereomers.

EXAMPLE 6

Analogously to Example 5,

6.1) from N-formyl-L-alanine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester therewas obtained

N-formyl-L-alanine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]pentenyl ester;

6.2) from N-formyl-L-phenylalanine(S)-1-[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentyl ester there wasobtained

N-formyl-L-phenylalanine(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-4-pentyl ester;

6.3) from N-formyl-L-leucine(S)-1-[[(2S,3S)-3-decyl-4-oxo-2-oxetanyl]methyl]-4-pentenyl ester therewas obtained

N-formyl-L-leucine(S)-1-[[(2S,3S)-3-decyl-4-oxo-2-oxetanyl]methyl]pentyl ester.

EXAMPLE 7

A solution of 67 mg of N-benzylcarbamoyl-leucine1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyldodecyl ester in 15 ml of THFwas hydrogenated in the presence of 10% Pd/C at room temperature under aH₂ atmosphere (normal pressure) until the reaction has finished. Theproduct obtained after filtration and evaporation was chromatographed onsilica gel. There was obtained pure leucine1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester m.p. 27°-30° C.

EXAMPLE 8

265 mg of a diastereomer mixture of3-hexyl-4-[(10Z,13Z)-2-[tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanone was dissolved in 2.5 ml ofethanol and 13 mg of pyridinium-4-toluenesulfonate were added. Thereaction mixture was heated to 55°-60° C. until the reaction wasfinished. The solvent was removed in vacuo and the residue was taken upin ether, whereby there separated crystals which was removed byfiltration. The solvent was evaporated off in vacuo and the residue waschromatographed on silica gel, whereby the products listed below wereeluted in the sequence given. The products, which were to some extentstill impure were purified by repeating the chromatography. In thismanner there were obtained:

8.1) ((3S,4S)-4-Hexyl-4-[(R,10Z,13Z)-2-hydroxy-10,13,-nonadecadienyl]2-oxetanone (diastereomer I) as a colorless oil, MS:M⁺ (434); IR: 3,420, 1,820, 1,120 cm⁻¹,

8.2) rac-trans-3-hexyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (diastereomer II) as a colorless oil, MS:M⁺ (434); IR: 3,448, 1,820 1,122 cm⁻¹ and

8.3) cis-3-hexyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (diastereomer III) as acolorless oil, MS: M⁺ (434): IR: 3,374, 1,822, 1,117 cm⁻¹.

EXAMPLE 9

Analogously to Example 8,

9.A.1) trans-3-ethyl-1-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone, MS: 360 (M⁺ -H₂ O), 334(M⁺ --CO₂), 316 (M⁺ H₂ O--W₂), IR: 3,446, 1,823, 1,122 cm⁻¹,

9.A.2) cis-3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (enantiomer mixture A), MS:378/M⁺); IR: 3,445 1,822, 1,116 cm⁻¹ and

9.A.3) cis-3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (enantiomer mixture B), MS:(chemical induction with NH ): 396 (M+NH₄ ⁺, 374 (M +H⁺); IR: 3,415,1,823, 1,115 cm⁻¹, were obtained

from a cis, trans mixture of3-ethyl-4-[(R,10Z,13Z)-2-[tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanone;

9.B. 3-ethyl-4-[(Z)-2-hydroxy-10-nonadecenyl]-2-oxetanone, MS: 362 (M⁺-H₂ O), 318 (M⁺ --H₂ O--CO₂); IR: 3,435, 1,823, 1,119 cm⁻¹, was obtained

from3-ethyl-4-[(Z)-2-[(tetrahydro-2H-pyran-2-yl)oxy]-10-nonadecenyl-2-oxetanone;9.C.1) (3S,4S)-3-benzyl-4-[(R,10Z,-13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone, MS: 440 M⁺); IR: 3,430, 1,822, 1,120cm⁻¹,

9.C.2). rac-trans-3-benzyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone, MS: 440 M⁺); IR: 3,512, 1,822, 1,123cm⁻¹ and

9 C.3) cis-3-benzyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl]-2-oxetanone (2 diastereomers), M.S.: 378 (M⁺ --CO₂--H₂ O), 287 (M⁺ --H₂ O--CO₂ -benzyl); IR: 3,420, 1,822, 1,134 cm⁻¹,were obtained

from a diastereomer mixture of3-benzyl-4-[(R,10Z,13Z)-2-[tetrahydro-2H-pyran-2-yl)oxy]-10,13-nonadecadienyl]-2-oxetanone:

9.D. (3S,4S)-3-hexyl-4-[(S)-8-hydroxy-p-phenoxyphenethyl]-2-oxetanonem.p. 51°-54° C., MS: 368 M⁺); IR: 3,486, 1,793, 1,245, 1,141, wasobtained

from(3S,4S)-3-hexyl-4-[(S)-p-phenoxy-β-[(tetrahydro-2H-pyran-2-yl)oxy]phenethyl]-2-oxetanone;

9.E. (3S,4S)-3-ethyl-4-[(S)-β-hydroxy-p-phenoxyphenethyl]-2-oxetanonem.p. 67°-70° C. MS: 312 M⁺); IR; 3,416, 1,835, 1,250, 1,108, wasobtained

from(3S,1S)-3-ethyl-1-[(S)-p-phenoxy-β-[(tetrahydro-2H-pyran-2-yl)oxy]phenethyl]-2-oxetanone.

9.F.1. rac-trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (2R,3S4S:2S,3R,4R), m.p. 44.5°-46°,

9.F.2. rac-trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone(2S,3S,4S:2R,3R,4R). m.p. 45.5°-47° C.,

9.F.3. rac-cis-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (enantiomerpair A), D.C. silica gel, hexane-ethyl acetate 9:1, RF=0.49, and

9 F.4. rac-cis-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (enantiomerpair B), D.C. silica gel, hexane-ethyl acetate 9:1, RF=0.46, wereobtained

from 3-hexyl-4-[2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanone:

9.G.1. (3S,4S)-3-hexyl-1-[(R)-2-hydroxytridecyl]-2-oxetanone, m.p.46°-46.5° C., and

9 G.2. (3R,4R)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, m.p46°-47°: [α]_(D) ²⁰ =+12° C. (CHCl₃, c=1.5), were obtained

from3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanone;

9.H. rac-trans-3-ethyl-4-(2-hydroxytridecyl)-2-oxetanone m.p. 35.5°-36°C., was obtained

from 3-ethyl-4-[2-[(tetrahydro-2H-pyran-2yl]oxy]tridecyl]-2-oxetanone;

9.I. trans-3-methyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, D.C. silicagel, hexane-ether 1:3, Rf=0.49, was obtained

from3-methyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl]oxy]tridecyl]-2-oxetanone;

9.J. rac-trans-3-allyl-4-[2-hydroxytridecyl]-2-oxetanone, D.C. silicagel, hexane-ethyl 1:1, Rf=0.39, was obtained

from 3-allyl-4-[2-(tetrahydro-2H-pyran-2-yl]oxy]tridecyl]-2-oxetanone;

9.K. trans-3-hexyl-4-[(R)-2-hydroxypropyl]-2-oxetanone, D.C. silica gel,hexane-ether 1:3, Rf=0.36, was obtained

from3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl]oxy]propyl]-2-oxetanone;

9.L. rac-trans-3-hexadecyl-4-(2-hydroxypropyl)-2-oxetanone, m.p. 37°-38°C., was obtained

from3-hexadecyl-4-[2-[(tetrahydro-2H-pyran-2-yl]oxy]propyl]-2-oxetanone;

9.M. rac-trans-3-hexyl-4-[-2-hydroxy-5-hexenyl]-2-oxetanone(2R,3S,4S:2S,3R,4R) was obtained

fromtrans-3-hexyl-4-[-2-[(tetrahydro-2H-pyran-2-yl)oxy]-5-hexenyl]-2-oxetanone

9.N. trans-3-decyl-4-[(R)-2-hydroxy-5-hexenyl-2-oxetanone was obtained

fromtrans-3-decyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl)oxy]hexenyl]-2-oxetanone;

9.O. trans-3-hexyl-4-((R)-2-hydroxy-5-tridecenyl)2-oxetanone wasobtained

fromtrans-3-hexyl-4-[(R)-2-[(tetrahydro-2H-pyran-2-yl]oxy]tridecenyl-2-oxetanone;

9.P. (S)-3-hexyl-(S)-4[(R)-2-hydroxy-5-hexenyl]-2-oxetanone was obtained

from3-hexyl-4-[[(R)-2-[(tetrahydro-2H-pyran-2-yl)-oxy]hexenyl]-2-oxetanone;9.Q. trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (diastereomermixture) was obtained

from 3-hexyl-4-[2-[tetrahydro-2H-pyran-2-yl)oxy]tridecyl]-2-oxetanone.

EXAMPLE 10 10.A. Manufacture of the Product

565 mg of N-[(benzyloxy)carbonyl]-L-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester weredissolved in 12 ml of THF. The mixture was hydrogenated at roomtemperature in the presence of 40 mg of 10% Pd/C. After the reaction wasfinished the catalyst was filtered off and the filtrate was evaporated.The residue was taken up in 9 ml of THF and 71 μl of formic acid/aceticacid anhydride were added dropwise. The mixture was diluted with 5 ml ofdiethyl ether and washed twice with 2% sodium hydrogen carbonatesolution and then with water. After drying over sodium sulfate it wasfiltered and evaporated. By chromatography on silica gel andrecrystallization from n-pentane there was obtained N-formyl-(S)-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2oxetanyl]methyl]octadecyl ester of m.p.60°-61° C.

10.B. Preparation of the Starting Material

10.B.a) As described in paragraph 10.B.e) hereinafter, a diastereomermixture which consisted of 85-90% of (R)-2-hydroxy-1,2,2-triphenylethyl(S,Z)-3-hydroxy-11-eicosenoate, m.p. 112°-114° C., was obtained

from oleyl aldehyde and (R)-α-(hydroxydiphenylmethyl)benzyl acetate.

10.B.b) As described in paragraph 10.B.f) hereinafter, methyl(S,Z)-3-hydroxy-11-eicosenoate was obtained as a colorless oil

from (R)-2-hydroxy-1,2,2-triphenylethyl(S,Z)-3-hydroxy-11-eicosenoate.

10.B.c) As described in paragraph J)a) above for the preparation of theesters of formula XV, methyl(S,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenoate, which contained10-15% of the (R)-isomer, was obtained from methyl(S,Z)-3-hydroxy-11-eicosenoate.

10.B.d) As described in paragraph I)a) above for the preparation of thealdehydes of formula VIII,(S,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenal, which contained10-15% of the corresponding (R)-isomer was obtained

from methyl (S,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenoate.

10.B.e) 7.7 g of (R)-α-(hydroxydiphenylmethyl)benzyl acetate weresuspended in 75 ml of THF under argon and cooled to about -75° C. Thissuspension was treated dropwise with a two-fold amount of a lithiumdiisopropylamide solution. The mixture was left to warm to 0° C. andstirred at this temperature for 10 minutes. The solution was then cooledto -113° to -117° C. and treated during the cooling with 230 ml ofdiethyl ether. A solution of(S,Z)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-11-eicosenal in 20 ml of diethylether was added dropwise to the solution and the mixture was stirred fora further 30 minutes. The mixture was treated dropwise with 20 ml ofsaturated ammonium chloride solution. The mixture was left to warm toroom temperature. The aqueous phase was separated and the organic phasewas washed three times with 80 ml of water and once with saturatedsodium chloride solution. After two-fold washing with 100 ml ofsaturated ammonium chloride solution the organic phase was dried oversodium sulfate, filtered and evaporated. By repeated recrystallizationfrom methanol there was obtained a diastereomer mixture which consistedmainly of (R)-2-hydroxy-1,2,2-triphenylethyl(3S,5S,13Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoate, m.p.91°-93° C.

10.B.f) 12.75 g of (R)-2-hydroxy-1,2,2-triphenylethyl(3S,5S,13Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoatewere suspended in 130 ml of methanol and treated with 17.5 ml of 1Nmethanolic sodium methylate solution. After the reaction was finishedthe mixture was poured into 650 ml of saturated ammonium chloridesolution and extracted several times with diethyl ether. After dryingover sodium sulfate the organic phase was filtered and evaporated, theresidue was taken up in 70 ml of n-hexane and stirred for 1 hour whilecooling in an ice-bath. The white crystals were filtered off undersuction and washed with n-hexane. The filtrate was evaporated and theresidue was chromatographed on silica gel. There was obtained adiastereomer mixture which consisted chiefly of methyl(3S,5S,13Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoate,IR: 3,473, 1,739, 1,076, 1,024 cm⁻¹. 10.B.g) As described in paragraphD)a) above for the preparation of the esters of formula VI, adiastereomer mixture, which contained chiefly methyl(2S,3S,5S,13Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2 H-pyran-2-yl)oxy]-13-docosenoate, was obtained as a colorless oil

from methyl(3S,5S,13Z)-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoateand ethyl iodide.

10.B.h) In analogy to Example 3 above, a diastereomer mixture, whichcontained chiefly methyl (2S,3S,5S)-2ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]docosanoate, IR: 1,738, 1,199, 1,167, 1,132, 1,115,1,176, 1,023 cm⁻¹, was obtained

from a diastereomer mixture which consisted chiefly of methyl(2S,3S,5S,13Z)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]-13-docosenoate.

10.B.i) 0.12 g of a diastereomer mixture, which consisted chiefly ofmethyl (2S,3S,5S)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]docosanoate, was stirred at room temperature in 2.5 ml of 2Nmethanolic potassium hydroxide solution until the reaction was finished.The turbid solution was poured into 10 ml of water and adjusted to pH 2with 2N hydrochloric acid. After extraction with diethyl ether theextract was dried over sodium sulfate, filtered and evaporated.Chromatography on silica gel gave a diastereomer mixture which consistedchiefly of (2S,3S,5S)-2-ethyl-3-hydroxy-5-[(tetrahydro-2 H-pyran-2-yl)oxy]docosanoic acid as a colorless oil, IR: 1,709 cm⁻¹.

10.B.j) As described in paragraph A.a) above for the preparation of theethers of formula IV, (3S,4S)-3-ethyl-4-[(S)-2-[(tetrahydro-2H-pyran-2-yl)oxy]nonadecyl]-2-oxetanone was obtained as the maincomponent of a diastereomer mixture as a colorless oil, IR: 1,826 cm⁻¹,

from a diastereomer mixture which consisted chiefly of(2S,3S,5S)-2-ethyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]docosanoic acid. 10.B.k) In analogy to Example 8,(3S,4S)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone, m.p. 82°-84° C.(MeOH), was obtained

from (3S,4S)-3-ethyl-4-[(S)-2-[(tetrahydro-2H-pyran-2-yl)oxy]nonadecyl]-2-oxetanone. 10.B.1) 796 mg ofN-[(benzyloxy)carbonyl]-L-leucine were dissolved in 10 ml of methylenechloride the solution was cooled to 2°-3° C. and 309 mg ofdicyclohexylcarbodiimide were added. After 15 minutes the white crystalswere filtered off under suction and washed with methylene chloride. Thefiltrate was evaporated at room temperature in vacuo and the residue wasdissolved in 7 ml of N,N-dimethylformamide (DMF). This solution wasadded to 574 mg of(3S,4S)-3-ethyl-4-[(S)-2-hydroxynonadecyl]-2-oxetanone and 22 mg of4-dimethyl-amino-pyridine in 6 ml of DMF. The mixture was stirred for 30minutes. The mixture was poured on to 100 ml of ice-water and extractedthree times with 20 ml of diethyl ether. The combined organic phaseswere dried over sodium sulfate, filtered and evaporated. Afterchromatography on silica gel there was obtainedN-[(benzyloxy)carbonyl]-L-leucine(S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester as whitecrystals of m.p. 44°-47° C.

EXAMPLE A

Manufacture of soft gelatine capsules of the following composition:

    ______________________________________                                                          Amount per capsule                                          ______________________________________                                        An oxetanone of formula I or III                                                                   50 mg                                                    NEOBEE M-5          450 μl                                                 ______________________________________                                    

The solution of the active substance in NEOBEE M-5 is filled into softgelatine capsules of suitable size.

NEOBEE M-5 is medium chain length triglyceride.

We claim:
 1. A compound of the formula ##STR25## wherein R¹ and R² areindependently C₁₋₁₇ -alkyl which is saturated or optionally interruptedby up to 8 double or triple bonds and/or optionally interrupted by an Oor S atom, which is present in other than the α-position to anunsaturated C atom; or phenyl, benzyl or --C₆ H₄ --X--C₆ H₅ring-substituted by 0 to 3 C₁₋₆ -alkyl-(O or S)₁ or 0 groups, and X isoxygen, sulfur or (CH₂)₀₋₃, with the proviso that when R¹ is n-hexyl andR² is undecyl or 2Z,5Z-undecadienyl, at least one of the asymmetricC-atoms present in the oxetanone ring and in the β-position to thelatter has the R-configuration, an enantiomer or a diastereomer thereof.2. A compound according to claim 1, wherein R¹ is methyl, propyl, hexyl,decyl, hexadecyl, allyl, benzyl or ethyl; and R² is methyl, undecyl,3-butenyl, 3-undecenyl, 8,11-heptadecadienyl, phenoxyphenyl orheptadecyl.
 3. A compound in accordance with claim 1,rac-trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (2S,3S,4S:2R,3R,4R).4. A compound in accordance with claim 1,(3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone.
 5. A pancreaslipase-inhibiting composition comprising an effective amount of aracemic compound of the formula ##STR26## wherein R¹ and R² areindependently C₁₋₁₇ -alkyl which is saturated or optionally interruptedby up to 8 double or triple bonds and/or optionally interrupted by an Oor S atom, which is present in other than the α-position to anunsaturated C. atom; or phenyl, benzyl or --C₆ H₄ --X--C₆ H₅ring-substituted by 0 to 3 C₁₋₆ -alkyl-(O or S)₁ or 0 groups, and X isoxygen, sulfur or (CH₂)₀₋₃, with the proviso that when R¹ is n-hexyl andR² is undecyl or 2Z,5Z-undecadienyl, at least one of the asymmetricC-atoms present in the oxetanone ring and in the β-position to thelatter has the R-configuration, an enantiomer or diastereomer thereof,or a pharmaceutically acceptable acid addition salt thereof, and apharmaceutically inert carrier material.
 6. A composition according toclaim 19, wherein R¹ is methyl, propyl, hexyl, decyl, hexadecyl, allyl,benzyl or ethyl; and R² is methyl, undecyl, 3-butenyl, 3-undecenyl,8,11-heptadecadienyl, phenoxyphenyl or heptadecyl.
 7. A composition inaccordance with claim 5, wherein the compound of formula III israc-trans-3-hexyl-4-(2-hydroxytridecyl)-2-oxetanone (2S,3S,4S:2R,3R,4R)or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1, wherein R¹ is ethyl.
 9. A compound according to claim 1,wherein R² is heptadecyl.